H9N2 cold-adapted (ca) vaccine: A Phase I study was initiated in 50 healthy adults who were admitted to an in-patient unit. The vaccine was safe and well tolerated but the level of replication was low. Although shedding of vaccine virus was minimal, 92% of seronegative participants had >4-fold rises in HI antibody titer and 79% had >4-fold rises in neutralizing antibody titer following two doses of vaccine; 100% had a response detected by at least one of these assays. Therefore, despite being highly restricted in replication, two doses of H9N2/AA ca vaccine were immunogenic in seronegative adults. [unreadable] H5N1 cold-adapted (ca) vaccines: Three candidate vaccines were developed based on H5N1 viruses isolated in 1997, 2003 and 2004. In each virus, the HA and NA genes were derived from wild-type H5N1 viruses. The HA in each case was modified to remove the multibasic amino acid cleavage site that is a virulence motif. A Phase I trial for safety, infectivity, and immunogenicity of the 2004 H5N1 Vaccine based on the A/VietNam/1203/2004 (H5N1) virus, was undertaken at a dose of 6.7 log10 TCID50 per dose in 20 healthy adults, aged 18-49 years. The clinical trial was conducted in an isolation unit. Subjects received two doses of vaccine, administered 28 to 62 days apart, and were sequestered in an isolation unit 3 weeks following both doses. The level of replication, infectivity, and immunogenicity of the vaccine virus at this dose was low. Therefore, a study was undertaken to evaluate the safety, infectivity and immunogenicity of a moderately higher dose (7.5 log10 TCID50) of the same vaccine. Nineteen subjects received two doses of this dose. The vaccine was safe & well tolerated. Analysis of data from this study is in progress.[unreadable] In order to determine whether the finding of low infectivity and low immunogenicity observed with the 2004 H5N1 ca virus was unique to this strain, a Phase I study was undertaken with the 2003 H5N1 ca vaccine. Sixteen subjects received 2 doses of the 2003 H5N1 ca vaccine. The vaccine was safe & well tolerated. Analysis of data from this study is in progress.[unreadable] H7N3 cold-adapted (ca) vaccine: Based on promising preclinical data in mice and ferrets, a Phase I study was undertaken to evaluate the safety, level of replication, infectivity and immunogenicity of an H7N3 ca vaccine based on A/chicken/British Columbia/CN-6/2004 (H7N3). Seventeen subjects received two doses of the vaccine. The vaccine was safe and generally well tolerated. Analysis of data from this study is in progress.[unreadable] H2N2 cold-adapted (ca) vaccine: H2N2 viruses caused the 1957 influenza pandemic and circulated in humans until 1968 when they were replaced by H3N2 viruses. Although H2 viruses have not circulated in humans since 1968, this subtype is maintained in avian reservoirs worldwide. An H2 vaccine is a high priority in preparing for a pandemic because H2 viruses have a proven capability for causing disease in humans and persons born after 1968 lack H2-specific immunity. Because the currently licensed live attenuated influenza vaccine utilized in the United States bears the internal protein genes of the influenza A/AnnArbor/6/60 (H2N2) ca virus, this virus was a logical first choice for evaluation as an H2 vaccine. However, this virus with the H2 HA and N2 NA has not been evaluated in seronegative people. An IND was submitted for a Phase I study to evaluate safety, level of replication, infectivity and immunogenicity of A/Ann Arbor/6/60 ca (H2N2) virus. This study is in progress.[unreadable] H6N1 cold-adapted (ca) vaccine: Based on promising preclinical data in mice and ferrets, an IND was submitted for a Phase I study to evaluate safety, level of replication, infectivity and immunogenicity of an H6N1 ca vaccine based on A/teal/Hong Kong/W312/1997 (H6N1). The study will be initiated in October 2008.